Recent advancements in nanomaterial-mediated ferroptosis-induced cancer therapy: Importance of molecular dynamics and novel strategies.

Ferroptosis is a novel type of controlled cell death resulting from an imbalance between oxidative harm and protective mechanisms, demonstrating significant potential in combating cancer. It differs from other forms of cell death, such as apoptosis and necrosis. Molecular therapeutics have hard time playing the long-acting role of ferroptosis induction due to their limited water solubility, low cell targeting capacity, and quick metabolism in vivo. To this end, small molecule inducers based on biological factors have long been used as strategy to induce cell death. Research into ferroptosis and advancements in nanotechnology have led to the discovery that nanomaterials are superior to biological medications in triggering ferroptosis. Nanomaterials derived from iron can enhance ferroptosis induction by directly releasing large quantities of iron and increasing cell ROS levels. Moreover, utilizing nanomaterials to promote programmed cell death minimizes the probability of unfavorable effects induced by mutations in cancer-associated genes such as RAS and TP53. Taken together, this review summarizes the molecular mechanisms involved in ferroptosis along with the classification of ferroptosis induction. It also emphasized the importance of cell organelles in the control of ferroptosis in cancer therapy. The nanomaterials that trigger ferroptosis are categorized and explained. Iron-based and noniron-based nanomaterials with their characterization at the molecular and cellular levels have been explored, which will be useful for inducing ferroptosis that leads to reduced tumor growth. Within this framework, we offer a synopsis, which traverses the well-established mechanism of ferroptosis and offers practical suggestions for the design and therapeutic use of nanomaterials.

Development and evaluation of multi-functionalized sialic acid conjugated asiatic acid nanoconstruct to mitigate cognitive deficits in Alzheimer's disease.

Sialic acid (SA) serves a critical role in neuronal repair and cognitive functions. SA is a nine-carbon carboxylated sugar with a glycoconjugate cap that acts as a ligand and surface decoration with SA facilitates delivery to the target site. The present research aimed to develop SA surface modified AA nanostructured lipid carrier (NLCs) with carbodiimide conjugation method. Sterylamine, poloxamer 188 and tween 80 were used as surfactants and several characterization studies including, differential scanning calorimetry, fourier transform infrared spectroscopy and x-ray photon spectroscopy were analyzed. Further, in vitro, neuroprotective efficiency was evaluated in SH-SY5Y cells and hCMEC/D3 cells and found significant potential effects with the treatments of developed NLCs. Pharmacodynamics studies were also assessed in beta-amyloid-injected rats following quantification of Alzheimer's disease (AD) hallmarks like, Aß(1-42), tau-protein, glycogen synthase kinase-3ß levels, interleukin-6 and tumor necrosis factor-α for neuroinflammatory responses. Characterization studies revealed the conjugation on developed NLCs. The in vitro and in vivo results showed significant effects of SA decorated NLCs in reversing the damage by toxicant which was further characterized by the levels of neurotransmitters like acetylcholinesterase, butyrylcholinesterase. The results revealed significant (p < .05) refurbishment of cholinergic functions after 28 days of treatment of developed NLCs. These preclinical findings support the use of SA as a ligand to deliver the AA at targeted site as well as to mitigate the cognitive deficits in AD.

Advances in 4D printing: from stimulation to simulation.

The advancement of four-dimensional (4D) printing has been fueled by the rise in demand for additive manufacturing and the expansion in shape-memory materials. The printing of smart substances that respond to external stimuli is known as 4D printing. 4D printing allows highly controlled shapes to simulate the physiological milieu by adding time dimensions. The 4D printing is suitable with current progress in smart compounds, printers, and its mechanism of action. The 4D printing paradigm, a revolutionary enhancement of 3D printing, was anticipated by various engineering disciplines. Tissue engineering, medicinal, consumer items, aerospace, and organ engineering use 4D printing technology. The current review mainly focuses on the basics of 4D printing and the methods used therein. It also discusses the time-dependent behavior of stimulus-sensitive compounds, which are widely used in 4D printing. In addition, this review highlights material aspects, specifically related to shape-memory polymers, stimuli-responsive materials (classified as physical, chemical, and biological), and modified materials, the backbone of 4D printing technology. Finally, potential applications of 4D printing in the biomedical sector are also discussed with challenges and future perspectives.

Sulfobutylether-ß-cyclodextrin: A functional biopolymer for drug delivery applications.

Sulfobutylether ß-cyclodextrin (SBE-ß-CD) is a polyanionic cyclic oligosaccharide that contains glucopyranose units forming a torus ring-like structure. SBE-ß-CD is gifted with many favorable properties viz. relatively high solubility (>50 folds compared to ß-CD), improved stability, and biocompatibility that praised SBE-ß-CD as a smart polymer for drug delivery applications. Commercially, SBE-ß-CD is popular by its brand name Captisol®. The present review discusses the structure, properties, and preparation methods of SBE-ß-CD-based inclusion complexes (ICs). Furthermore, we discuss here the preparation and applications of SBE-ß-CD ICs-based nanoparticulate drug delivery systems, which combines the merits of both, ICs (enhanced solubility) and nanoparticles (NPs, targeted therapy). Patents on and FDA-approved Captisol®-enabled products are tabulated in the benefit of readers. The toxicological aspects and current clinical status of SBE-ß-CD or SBE-ß-CD-based products are briefly explained in the present review. In our opinion, the present review would be a pathfinder to allow dissemination of information on SBE-ß-CD.

2D Hetero-Nanoconstructs of Black Phosphorus for Breast Cancer Theragnosis: Technological Advancements.

As per global cancer statistics of 2020, female breast cancer is the most commonly diagnosed cancer and also the foremost cause of cancer death in women. Traditional treatments include a number of negative effects, making it necessary to investigate novel smart drug delivery methods and identify new therapeutic approaches. Efforts for developing novel strategies for breast cancer therapy are being devised worldwide by various research groups. Currently, two-dimensional black phosphorus nanosheets (BPNSs) have attracted considerable attention and are best suited for theranostic nanomedicine. Particularly, their characteristics, including drug loading efficacy, biocompatibility, optical, thermal, electrical, and phototherapeutic characteristics, support their growing demand as a potential substitute for graphene-based nanomaterials in biomedical applications. In this review, we have explained different platforms of BP nanomaterials for breast cancer management, their structures, functionalization approaches, and general methods of synthesis. Various characteristics of BP nanomaterials that make them suitable for cancer therapy and diagnosis, such as large surface area, nontoxicity, solubility, biodegradability, and excellent near-infrared (NIR) absorption capability, are discussed in the later sections. Next, we summarize targeting approaches using various strategies for effective therapy with BP nanoplatforms. Then, we describe applications of BP nanomaterials for breast cancer treatment, which include drug delivery, codelivery of drugs, photodynamic therapy, photothermal therapy, combined therapy, gene therapy, immunotherapy, and multidrug resistance reversal strategy. Finally, the present challenges and future aspects of BP nanomaterials are discussed.

Long-acting formulation strategies for protein and peptide delivery in the treatment of PSED.

The invigoration of protein and peptides in serious eye disease includes age-related macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. The transportation of macromolecules like aptamers, recombinant proteins, and monoclonal antibodies to the posterior segment of the eye is challenging due to their high molecular weight, rapid degradation, and low solubility. Moreover, it requires frequent administration for prolonged therapy. The long-acting novel formulation strategies are helpful to overcome these issues and provide superior therapy. It avoids frequent administration, improves stability, high retention time, and avoids burst release. This review briefly enlightens posterior segments of eye diseases with their diagnosis techniques and treatments. This article mainly focuses on recent advanced approaches like intravitreal implants and injectables, electrospun injectables, 3D printed drug-loaded implants, nanostructure thin-film polymer devices encapsulated cell technology-based intravitreal implants, injectable and depots, microneedles, PDS with ranibizumab, polymer nanoparticles, inorganic nanoparticles, hydrogels and microparticles for delivering macromolecules in the eye for intended therapy. Furthermore, novel techniques like aptamer, small Interference RNA, and stem cell therapy were also discussed. It is predicted that these systems will make revolutionary changes in treating posterior segment eye diseases in future.

Organic quantum dots: An ultrasmall nanoplatform for cancer theranostics.

Tumours are the second leading cause of death globally, generating alterations in biological interactions and, as a result, malfunctioning of crucial genetic traits. Technological advancements have made it possible to identify tumours at the cellular level, making transcriptional gene variations and other genetic variables more easily investigated. Standard chemotherapy is seen as a non-specific treatment that has the potential to destroy healthy cells while also causing systemic toxicity in individuals. As a result, developing new technologies has become a pressing necessity. QDs are semiconductor particles with diameters ranging from 2 to 10 nanometers. QDs have grabbed the interest of many researchers due to their unique characteristics, including compact size, large surface area, surface charges, and precise targeting. QD-based drug carriers are well known among the many nanocarriers. Using QDs as a delivery approach enhances solubility, lengthens retention time, and reduces the harmful effects of loaded medicines. Several varieties of quantum dots used in drug administration are discussed in this article, along with their chemical and physical characteristics and manufacturing methods. Furthermore, it discusses the role of QDs in biological, medicinal, and theranostic applications.

Advancements in cell membrane camouflaged nanoparticles: A bioinspired platform for cancer therapy.

The idea of employing natural cell membranes as a coating medium for nanoparticles (NPs) endows man-made vectors with natural capabilities and benefits. In addition to retaining the physicochemical characteristics of the NPs, the biomimetic NPs also have the functionality of source cell membranes. It has emerged as a promising approach to enhancing the properties of NPs for drug delivery, immune evasion, imaging, cancer-targeting, and phototherapy sensitivity. Several studies have been reported with a multitude of approaches to reengineering the surface of NPs using biological membranes. Owing to their low immunogenicity and intriguing biomimetic properties, cell-membrane-based biohybrid delivery systems have recently gained a lot of interest as therapeutic delivery systems. This review summarises different kinds of biomimetic NPs reported so far, their fabrication aspects, and their application in the biomedical field. Finally, it briefs on the latest advances available in this biohybrid concept.

Cationic biopolymer decorated Asiatic Acid and Centella asiatica extract incorporated liposomes for treating early-stage Alzheimer's disease: An In-vitro and In-vivo investigation.

Background: Asiatic acid (AA) is a naturally occurring triterpenoid derivative of Centella asiatica (CA) with neuroprotective effect. The study aimed to design an ideal oral drug delivery system to treat Alzheimer's disease (AD) and develop chitosan-embedded liposomes comprising an extract of CA (CLCAE) and compare them with the chitosan-coated liposomes of asiatic acid (CLAA) for oral delivery to treat the initial phases of AD.  Methods: The solvent evaporation technique was used to develop CLCAE and CLAA, optimised with the experiment's design, and was further evaluated. Results: Nuclear magnetic resonance (NMR) studies confirmed coating with chitosan. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) indicated the successful formation of CLCAE and CLAA. Differential scanning colorimetry (DSC) confirmed the drug-phospholipid complex. Furthermore, the rate of  in vitro release of CLCAE and CLAA was found to be 69.43±0.3 % and 85.3±0.3 %, respectively, in 24 h.  Ex vivo permeation of CLCAE and CLAA was found to be 48±0.3 % and 78±0.3 %, respectively. In the Alcl3-induced AD model in rats, disease progression was confirmed by Y-maze, the preliminary histopathology evaluation showed significantly higher efficacy of the prepared liposomes (CLCAE and CLAA) compared to the Centella asiatica extract (CAE) and they were found to have equivalent efficacy to the standard drug (rivastigmine tartrate). The considerable increase in pharmacodynamic parameters in terms of neuronal count in the CLAA group indicated the protective role against Alcl3 toxicity and was also confirmed by assessing acetylcholine (Ach) levels. The pharmacokinetic study, such as C max, T max, and area under curve (AUC) parameters, proved an increase in AA bioavailability in the form of CLAA compared to the pure AA and CLCAE forms. Conclusion: The preclinical study suggested that CLAA was found to have better stability and an ideal oral drug delivery system to treat AD.

Stimuli responsive and receptor targeted iron oxide based nanoplatforms for multimodal therapy and imaging of cancer: Conjugation chemistry and alternative therapeutic strategies.

Cancer being one of the most precarious and second most fatal diseases evokes opportunities for multimodal delivery platforms which will act synergistically for efficient cancer treatment. Multifunctional iron oxide magnetic nanoparticles (IONPs) are being studied for few decades and still attracting increasing attention for several biomedical applications owing to their multifunctional design and intrinsic magnetic properties that provide a multimodal theranostic platform for cancer therapy, monitoring and diagnosis. The review article aims to provide brief information on various surface chemistries involved in modulating IONPs properties to exhibit potential therapy in cancer treatment. The review addresses structural, magnetic, thermal and optical properties of IONPs which aids in the fabrication of efficient multimodal nanoplatform in cancer therapy. The review discussed the pharmacokinetics of IONPs and attributes influencing them. This review inculcates recent advancements in therapies, focused on tumor-microenvironment-responsive and targeted therapy along with their eminent role in cancer diagnosis. The concept of stimuli-responsive including endogenous, exogenous and dual/multi stimuli-based delivery platform demonstrated significantly enhanced anticancer therapy. Several therapeutic approaches viz. chemotherapy, radiotherapy, immunotherapy, hyperthermia, gene therapy, sonodynamic therapy, photothermal, photodynamic-based therapy along with biosensing and several toxicity aspects of IONPs have been addressed in this review for effective cancer treatment.

Hot-Melt Extrusion: An Emerging Technique for Solubility Enhancement of Poorly Water-Soluble Drugs.

The solubility of the drug is a significant aspect to be considered during manufacturing of pharmaceutical products. Poor aqueous solubility of drugs imparts depleted bioavailability. In this regard, several techniques are available for enhancing drug solubility or dissolution. However, only few of them are scalable and industrially applicable. Hot-melt extrusion (HME) is one such technique that has been widely used in the industry. It is a single-step, continuous manufacturing, and scalable method that has proved successful in improving the solubility of poorly soluble drugs. This review highlights the numerous pharmaceutical applications of HME, such as formulations of sterile implants, taste masking of unpleasant drugs, cocrystallization, salt formation, sustained and controlled release formulations, etc. It also describes various hydrophilic and hydrophobic carriers utilized in HME. This review also briefly discusses the recent advances in HME and gives an update on the currently available marketed products. The opportunities and challenges in future development of pharmaceutical products by HME technique are also discussed.

Emerging Nanomedicines for the Treatment of Atopic Dermatitis.

Globally, the prevalence of Atopic dermatitis (AD) is significantly increasing and affecting around 20% of population including children. Complex interactions amongst abnormality in epidermal barrier function, environment, infectious agents and immunological defects are considered as key factors in the pathogenesis of AD. Although the role of oxidative stress has been studied in some skin diseases, investigation of the same in AD is intermittent. Calcineurin inhibitors and/or topical corticosteroids are currently available; however, it causes atrophy of the skin, burning sensation, and systemic side effects which leads to poor patient compliance. These limitations provoke the strong need to develop an innovative approach in managing AD. Nanomaterials for effective drug delivery to skin conditions such as AD have attracted a lot of attention owing to its ability to encapsulate, protect, and release the cargo at the diseased skin site. However, there are lots of unmet challenges especially in terms of development of non-toxic formulations and clinical translation of established nanomedicines in the form of accessible products. Numerous formulations have emerged as carrier for poorly soluble and permeable drugs, viz., lipidic, polymeric, metal, silica, liposomes, hydrocarbon gels and this field is evolving. This review is intended to provide an insight incidences associated with pathophysiology of AD and challenges with existing treatments of AD. Focus is kept on reviewing current development and emerging nanomedicines for effective treatment of AD. The review also inculcates merits of several nanomedicines in overcoming challenges of existing products and its future implications.

Molybdenum-based hetero-nanocomposites for cancer therapy, diagnosis and biosensing application: Current advancement and future breakthroughs.

In recent years, there have been significant advancements in the nanotechnology for cancer therapy. Even though molybdenum disulphide (MoS2)-based nanocomposites demonstrated extensive applications in biosensing, bioimaging, phototherapy, the review article focusing on MoS2 nanocomposite platform has not been accounted for yet. The review summarizes recent strategies on design and fabrication of MoS2-based nanocomposites and their modulated properties in cancer treatment. The review also discussed several therapeutic strategies (photothermal, photodynamic, immunotherapy, gene therapy and chemotherapy) and their combinations for efficient cancer therapy along with certain case studies. The review also inculcates various diagnostic techniques viz. magnetic resonance imaging, computed tomography, photoacoustic imaging and fluorescence imaging for diagnosis of cancer.

Overcoming Biological Barriers With Block Copolymers-Based Self-Assembled Nanocarriers. Recent Advances in Delivery of Anticancer Therapeutics.

Cancer is one of the most common life-threatening illness and it is the world's second largest cause of death. Chemotherapeutic anticancer drugs have many disadvantages, which led to the need to develop novel strategies to overcome these shortcomings. Moreover, tumors are heterogenous in nature and there are various biological barriers that assist in treatment reisistance. In this sense, nanotechnology has provided new strategies for delivery of anticancer therapeutics. Recently, delivery platforms for overcoming biological barriers raised by tumor cells and tumor-bearing hosts have been reported. Among them, amphiphilic block copolymers (ABC)-based self-assembled nanocarriers have attracted researchers worldwide owing to their unique properties. In this work, we addressed different biological barriers for effective cancer treatment along with several strategies to overcome them by using ABC-based self-assembled nanostructures, with special emphasis in those that have the ability to act as responsive nanocarriers to internal or external environmental clues to trigger release of the payload. These nanocarriers have shown promising properties to revolutionize cancer treatment and diagnosis, but there are still challenges for their successful translation to clinical applications.

Cationic biopolymer functionalized nanoparticles encapsulating lutein to attenuate oxidative stress in effective treatment of Alzheimer's disease: A non-invasive approach.

Present investigation explores cationic biopolymer core/shell nanoparticles (Chitosan@PLGA C/SNPs) for delivering carotenoids to brain via intranasal route for supressing oxidative stress in Alzheimer's disease (AD). The prepared C/SNPs exhibited particle size less than 150 nm with more than 80% of entrapment efficiency. Surface morphology confirmed uniform coating of shell (chitosan) over core PLGA NPs and suggested spherical nature and homogenous dispersion of C/SNPs. In-vitro release study demonstrated sustained release of lutein while C/SNPs permeation enhancement was confirmed by ex-vivo diffusion study. The study also investigated effect of cationic-shell with respect to anionic-core NPs on biocompatibility, cellular uptake, uptake mechanism, reactive-oxygen species (ROS) generation, ROS scavenging activity, blood-brain-barrier (BBB) permeation. The cellular uptake revealed enhanced internalization of nanoparticles via caveolae-mediated endocytosis. In-vitro co-culture model of BBB demonstrated efficient passage for C/SNPs through BBB. Antioxidant assay demonstrated significant ROS scavenging activity of C/SNPs. In-vivo pharmacokinetic and bio-distribution was performed along with in-vivo toxicity and stability. In-vivo toxicity demonstrated absence of any significant toxicity. Photo and thermal stability confirmed protection of lutein by C/SNPs. C/SNPs were highly deposited in brain following intranasal route. The obtained results demonstrate the potential application of cationic C/SNPs for attenuating oxidative stress in brain for effective AD therapy.

Two dimensional carbon based nanocomposites as multimodal therapeutic and diagnostic platform: A biomedical and toxicological perspective.

Graphene based nanocomposites have revolutionized cancer treatment, diagnosis and imaging owing to its good compatibility, elegant flexibility, high surface area, low mass density along with excellent combined additive effect of graphene with other nanomaterials. This review inculcates the type of graphene based nanocomposites and their fabrication techniques to improve its properties as photothermal and theranostic platform. With decades' efforts, many significant breakthroughs in the method of synthesis and characterization in addition to various functionalization options of graphene based nanocomposite have paved a solid foundation for their potential applications in the cancer therapy. This work intends to provide a thorough, up-to-date holistic discussion on correlation of breakthroughs with their biomedical applications and illustrate how to utilize these breakthroughs to address long-standing challenges in the clinical translation of nanomedicines. This review also emphasizes on graphene based nanocomposites based toxicity concerns pertaining to delivery platforms.

Intranasal Delivery of Nanotherapeutics/ Nanobiotherapeutics for the Treatment of Alzheimer's Disease: A Proficient Approach.

Therapeutics and biotherapeutics-based fabrication of nanoparticles has fascinated scientists since the past two decades and exciting challenges have been surmounted. Particular interest has been paid to the exploitation of functionalized nanocarriers in the treatment of Alzheimer's disease (AD) using nasal route. Development of various material-based nanocarriers is a common approach to obtain advanced drug delivery systems possessing the ability to follow intranasal (IN) route for brain targeting, which would ultimately ameliorate the effect of AD. This review highlights the various pathological theories for AD along with their controversies. This work intends to provide a thorough, up-to-date, and holistic discussion on various pathways for nose-to-brain delivery and different formulation factors impacting on nasal absorption. The various material properties and their engineered nanocarriers as a smart delivery system, including synergistic effect of therapeutic/biotherapeutic agent in IN delivery as well as in AD therapy have been discussed. This review also emphasizes toxicity, especially neurotoxicity concerns pertaining to drug delivery systems.

Polymeric Immunonanoparticles Mediated Cancer Therapy: Versatile Nanocarriers for Cell-Specific Cargo Delivery.

The major drawback with conventional therapeutic approaches for cancer therapy is decreased efficacy and redundant therapy associated toxicity and side effects causing increased patient discomfort. With the aim of minimizing these limitations, a vast amount of attention has been given to targeted nanocarrier-based drug delivery systems that possess a several-fold advantage over conventional therapy. Increased research in targeted nanoparticulate systems has led to the development of immunonanoparticles with enhanced efficacy and targeting efficiency along with decreased drug-resistant cancer- and dose-related toxicity. These immunonanoparticle- based therapies, which can be extended to immunotherapy, have gained wide attention, but few formulations will be approved by regulatory agencies in the near future. This review details the various immunonanoparticle systems explored in cancer therapy, with particular emphasis on polymeric nanoparticles. This review describes the mechanisms of immunotherapy and the pathways for targeting dendritic cells for immunotherapy. It also focuses on present status of clinical trials of immunonanoparticles and related patents, as well as various FDA-approved monoclonal antibodies (mAbs) for immunotherapy. Toxicity issues related to immunonanoparticles along with regulatory guidelines for these therapeutic nanoparticles are also discussed.

Box-Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: stability assessment.

Bicalutamide (BCM) is an anti-androgen drug used to treat prostate cancer. In this study, nanostructured lipid carriers (NLCs) were chosen as a carrier for delivery of BCM using Box-Behnken (BB) design for optimizing various quality attributes such as particle size and entrapment efficiency which is very critical for efficient drug delivery and high therapeutic efficacy. Stability of formulated NLCs was assessed with respect to storage stability, pH stability, hemolysis, protein stability, serum protein stability and accelerated stability. Hot high-pressure homogenizer was utilized for formulation of BCM-loaded NLCs. In BB response surface methodology, total lipid, % liquid lipid and % soya lecithin was selected as independent variable and particle size and %EE as dependent variables. Scanning electron microscopy (SEM) was done for morphological study of NLCs. Differential scanning calorimeter and X-ray diffraction study were used to study crystalline and amorphous behavior. Analysis of design space showed that process was robust with the particle size less than 200 nm and EE up to 78%. Results of stability studies showed stability of carrier in various storage conditions and in different pH condition. From all the above study, it can be concluded that NLCs may be suitable carrier for the delivery of BCM with respect to stability and quality attributes.